Brush amphiphilic block copolymers, and self-assembled nanoparticles therefrom

Abstract

The present application relates to brush amphiphilic block copolymers comprising at least one block which is hydrophilic and at least another block which is hydrophobic. The block copolymers can be used to prepare nanoparticles for biomedical applications including delivery of pharmaceuticals and other bioactive agents

The invention claimed is: 
     
       1. A brush amphiphilic block copolymer, comprising
 a) at least one hydrophilic block comprising between 2 and 1000 monomeric units of: 
 
       
         
           
           
               
               
           
         
         wherein 
         R 1  is H or (C 1 -C 6 )-alkyl, optionally substituted with —COOR or —CON(R) 2 , wherein R is independently or simultaneously H or (C 1 -C 6 )-alkyl; 
         R 2  is H, (C 1 -C 20 )-alkyl, (C 2 -C 24 )-alkenyl, (C 2 -C 24 )-alkynyl, (C 6 -C 14 )-aryl, (C 5 -C 14 )-heteroaryl, or (C 1 -C 10 )-alkylene-(C 6 -C 14 )-aryl, wherein the latter 6 groups:
 (i) are optionally substituted with halo, OH, or (C 1 -C 6 )-alkyl; 
 (ii) 1-3 carbon atoms are optionally replaced with O, NR′, or C(═O); and/or 
 (iii) optionally contain one or more functional groups comprising esters, thioesters, amides, ureas, thioureas, carbonates, carbamates, thiocarbamates, ethers, thioethers, primary, secondary, tertiary and/or quaternary amines, disulfides, sulfone, sulfonate, phosphoesters, phosphoramidates, phosphazenes, a hydrophilic or hydrophobic polymer, heterocycles, or triazoles; 
 
         Z is O, NR′ or S; 
         R′ is H or (C 1 -C 6 )-alkyl; and 
         n is 0 or at least 2; 
         b) at least one hydrophobic block comprising between 2 and 1000 monomeric units of 
       
       
         
           
           
               
               
           
         
         wherein 
         R 3  is H or (C 1 -C 6 )-alkyl, optionally substituted with —COOR or —CON(R) 2 , wherein R is independently or simultaneously H or (C 1 -C 6 )-alkyl; 
         L is a linker; 
         Q is a hydrophobic polymer or copolymer; and 
         R 5  is H, (C 1 -C 20 )-alkyl, (C 2 -C 24 )-alkenyl, (C 2 -C 24 )-alkynyl, (C 6 -C 14 )-aryl, (C 5 -C 14 )-heteroaryl, or (C 1 -C 10 )-alkylene-(C 6 -C 14 )-aryl, wherein the latter 6 groups:
 (i) are optionally substituted with halo, OH, or (C 1 -C 6 )-alkyl; 
 (ii) 1-3 carbon atoms are optionally replaced with O, NR′, or C(═O); and/or 
 (iii) optionally contain one or more functional groups comprising esters, thioesters, amides, ureas, thioureas, carbonates, carbamates, thiocarbamates, ethers, thioethers, primary, secondary, tertiary and/or quaternary amines, sulfone, sulfonate, phosphoesters, phosphoramidates, phosphazenes, a hydrophilic or hydrophobic polymer, heterocycles or triazoles. 
 
       
     
     
       2. The brush amphiphilic block copolymer of  claim 1 , wherein R 1  is H or (C 1 -C 3 )-alkyl, optionally substituted with —COOH. 
     
     
       3. The brush amphiphilic block copolymer of  claim 1 , wherein R 2  is H, (C 1 -C 6 )-alkyl, (C 6 )-aryl, (C 5 -C 6 )-heteroaryl, or (C 1 -C 3 )-alkylene-(C 6 )-aryl, the latter four groups are
 (i) are optionally substituted with (C 1 -C 3 )-alkyl; 
 (ii) 1-3 carbon atoms are optionally replaced with C(═O); and/or 
 (iii) optionally contain one or more functional groups comprising esters, thioesters, amides, ureas, thioureas, carbonates, carbamates, thiocarbamates, ethers, thioethers, primary, secondary, tertiary and/or quaternary amines, disulfides, sulfone, sulfonate, phosphoesters, phosphoramidates, phosphazenes, a hydrophilic or hydrophobic polymer and/or a heterocycle. 
 
     
     
       4. The brush amphiphilic block copolymer of  claim 1 , wherein n is an integer between 2 and 50. 
     
     
       5. The brush amphiphilic block copolymer of  claim 1 , wherein the monomeric units of the hydrophilic block has the structure 
       
         
           
           
               
               
           
         
         wherein R 1  is H or (C 1 -C 6 )-alkyl. 
       
     
     
       6. The brush amphiphilic block copolymer of  claim 1 , wherein the hydrophobic polymer or copolymer is a polyurethane, polythiourethane, polyether, polyamide, polyester, polyphosphazine, polyphosphamide, polyphosphodiester, polyureas, polythiourea, polyfumurates, or polyanhydride. 
     
     
       7. The brush amphiphilic block copolymer of  claim 1 , wherein the linker L is (C 1 -C 20 )-alkyl, (C 2 -C 24 )-alkenyl, (C 2 -C 24 )-alkynyl, (C 6 -C 14 )-aryl, (C 5 -C 14 )-heteroaryl, or (C 1 -C 10 )-alkylene-(C 6 -C 14 )-aryl, wherein the latter 6 groups
 (i) are optionally substituted with halo, OH, COOH, or (C 1 -C 6 )-alkyl; 
 (ii) 1-3 carbon atoms are optionally replaced with O, NR′, or C(═O); and/or 
 (iii) optionally contain one or more functional groups comprising esters, thioesters, amides, ureas, thioureas, carbonates, carbamates, thiocarbamates, ethers, thioethers, primary, secondary, tertiary and/or quaternary amines, disulfides, sulfone, sulfonate, phosphoesters, phosphoramidates, phosphazenes, a hydrophilic or hydrophobic polymer, heterocycle or triazoles. 
 
     
     
       8. The brush amphiphilic block copolymer of  claim 1 , wherein the at least one hydrophobic block comprises monomeric units of 
       
         
           
           
               
               
           
         
         wherein 
         R 3  is H or (C 1 -C 6 )-alkyl, optionally substituted with —COOR or —CON(R) 2 , wherein R is independently or simultaneously H or (C 1 -C 6 )-alkyl; 
         each R 4  is independently or simultaneously H, OH, COOH, (C 1 -C 10 )-alkyl, or aryl, wherein the latter two groups may optionally contain functional groups which are esters, acids, thioesters, amides, ureas, thioureas, carbonates, carbamates, thiocarbamates, ethers, thioethers, primary, secondary, tertiary and/or quaternary amines, disulfides, sulfonamides, sulfones, sulfonates, phosphoesters, phosphoramidates, phosphazenes, a hydrophilic or hydrophobic polymer and/or a heterocycle; 
         R 5  is H, (C 1 -C 20 )-alkyl, (C 2 -C 24 )-alkenyl, (C 2 -C 24 )-alkynyl, (C 6 -C 14 )-aryl, (C 5 -C 14 )-heteroaryl, or (C 1 -C 10 )-alkylene-(C 6 -C 14 )-aryl, wherein the latter 6 groups:
 (i) are optionally substituted with halo, OH, or (C 1 -C 6 )-alkyl; 
 (ii) 1-3 carbon atoms are optionally replaced with O, NR′, or C(═O); and/or 
 (iii) optionally contain one or more functional groups comprising esters, thioesters, amides, ureas, thioureas, carbonates, carbamates, thiocarbamates, ethers, thioethers, primary, secondary, tertiary and/or quaternary amines, disulfides, sulfone, sulfonate, phosphoesters, phosphoramidates, phosphazenes, a hydrophilic or hydrophobic polymer and/or triazoles; 
 
         L is a linker; 
         X and Y are independently or simultaneously O, NR′ or S; 
         W is O or NR′; 
         R′ is H or (C 1 -C 6 )-alkyl; 
         each p is independently or simultaneously 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; and 
         m is at least 2. 
       
     
     
       9. The brush amphiphilic block copolymer of  claim 1 , wherein R 3  is H or (C 1 -C 3 )-alkyl, optionally substituted with —COOH. 
     
     
       10. The brush amphiphilic block copolymer of  claim 1 , wherein R 5  is H, (C 1 -C 6 )-alkyl, (C 6 )-aryl, (C 5 -C 6 )-heteroaryl, or (C 1 -C 3 )-alkylene-(C 6 )-aryl, the latter four groups are
 (i) are optionally substituted with (C 1 -C 3 )-alkyl; 
 (ii) 1-3 carbon atoms are optionally replaced with C(═O); and/or 
 (iii) optionally contain one or more functional groups comprising esters, thioesters, amides, ureas, thioureas, carbonates, carbamates, thiocarbamates, ethers, thioethers, primary, secondary, tertiary and/or quaternary amines, disulfides, sulfone, sulfonate, phosphoesters, phosphoramidates, phosphazenes, a hydrophilic or hydrophobic polymer and/or a heterocycle. 
 
     
     
       11. The brush amphiphilic block copolymer of  claim 8 , wherein each R 4  is independently or simultaneously H, (C 1 -C 6 )-alkyl, or (C 6 -C 14 )-aryl, wherein the latter two groups may optionally contain esters, acids, thioesters, amides, ureas, thioureas, carbonates, carbamates, thiocarbamates, ethers, thioethers, primary, secondary, tertiary and/or quaternary amines, disulfides, sulfonamides, sulfones, sulfonates, phosphoesters, phosphoramidates, phosphazenes and/or a heterocycle. 
     
     
       12. The brush amphiphilic block copolymer of  claim 8 , wherein p is 1, 2, 3, 4, 5, 6, 7 or 8. 
     
     
       13. The brush amphiphilic block copolymer of  claim 1 , further comprising one or more additional monomers having the structure 
       
         
           
           
               
               
           
         
         wherein 
         R 6  is H or (C 1 -C 6 )-alkyl, optionally substituted with —COOR, wherein R is H or (C 1 -C 6 )-alkyl; and 
         K is a functional group which is —R″, —OR″, —SR″, —COOH, —COOR″, CON(R″) 2 , —S—S—R″, —R″OR″, —R″SR″, —R″COOR″, R″CON(R″) 2 , R″—S—S—R″, wherein R″ is (C 1 -C 10 )-alkenyl, (C 2 -C 10 )-alkynyl, (C 6 -C 10 )-aryl, (C 5 -C 10 )-heteroaryl, or (C 1 -C 10 )-alkylene-(C 6 -C 10 )-aryl. 
       
     
     
       14. The brush amphiphilic block copolymer of  claim 13 , wherein R″ is (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl, (C 2 -C 6 )-alkynyl, (C 6 )-aryl, (C 5 -C 6 )-heteroaryl, or (C 1 -C 6 )-alkylene-(C 6 )-aryl. 
     
     
       15. A nanoparticle prepared via the self-assembly or directed assembly of the block copolymers as claimed in  claim 1 . 
     
     
       16. The nanoparticle of  claim 15 , wherein the nanoparticle is prepared by flash nanoprecipitation. 
     
     
       17. The nanoparticle of  claim 15 , further comprising a drug or bioactive agent, wherein the drug or bioactive agent is encapsulated by the nanoparticle. 
     
     
       18. A method for the delivery of a drug or bioactive agent, comprising administering to a patient in need thereof, as nanoparticle as claimed in  claim 17 .